2014 National Aspirin Recommendations

Kaiser Permanente National Aspirin Recommendations Aspirin Therapy* for people without ASCVD (adapted from USPSTF): •

Initiate aspirin in men age 45-69 years and women age 55-69 years with ≥ 15% ASCVD Risk

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Consider aspirin in men age 45-59 years and women age 55-59 years with 5-14.9% ASCVD Risk

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Consider aspirin in men and women age 60-69 years with 10-14.9% ASCVD Risk

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Consider aspirin in men and women age 70-79 years with ≥ 15% ASCVD Risk

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Aspirin is not recommended in men < 45 years and women < 55 years of age

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There is no recommendation for or against aspirin therapy in men and women ≥ 80 years of age

Aspirin Therapy for people with ASCVD: For people with peripheral arterial disease (PAD), carotid stenosis, or abdominal aortic aneurysm (AAA): •

Initiate aspirin in individuals with symptomatic atherosclerotic peripheral arterial disease (claudication, revascularization or end-organ damage) or repaired AAA.

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Consider aspirin in individuals with subclinical atherosclerotic peripheral arterial disease (includes calcifications or stenosis, abnormalities of carotid intimal medial thickness (IMT), abnormal ankle-brachial index (ABI), and AAA that have had no repair, no revascularization, or no end-organ damage).

For people with CAD •

Initiate aspirin in individuals with coronary artery disease.

*Aspirin 81 mg orally daily

Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

2014 National Aspirin Recommendations

Aspirin Therapy for people without ASCVD Rationale: There is a need to explicitly consider both benefits and hams in our National Kaiser Permanente Aspirin recommendations for primary prevention of atherosclerotic cardiovascular disease (ASCVD). In 2009, the USPSTF published a guideline on the use of aspirin for the prevention of cardiovascular disease with recommendations based on the balance of risks and harms that are based on age, gender, and are cardiovascular event specific. To determine whether the potential benefit of ASCVD events (fatal and nonfatal heart attacks and strokes) prevented outweighs the potential harm of increased GI hemorrhage, both 10-year ASCVD risk and age must be considered. The risk of GI bleeds increases with advancing age. For men age 45-59 years the estimated 10-year risk of GI bleeds is 8 per 1000 men; is 24 per 1000 men age 60-69; and is 36 per 1000 men age 70-79. The estimated 10-year risk of GI bleeds is 4 per 1000 women age 55-59; is 12 per 1000 women age 60-69; and is 18 per 1000 women age 70-79. The risks above apply to adults who are not taking NSAIDs and who do not have upper GI pain or a history of GI ulcers. NSAID use and history of GI ulcers raise the risk of serious GI bleeding considerably and should be considered in determining the balance of benefits and harms. NSAID use combined with aspirin use approximately quadruples the risk of serious GI bleeding compared to the risk with aspirin use alone. The rate of serious bleeding in aspirin users is approximately 2-3 times higher in patients with a history of GI ulcers. Shared decision making is strongly encouraged with individuals whose risk is close to (either above or below) the estimates of 10-year risk levels indicated above. As the potential ASCVD benefit increases above harms, the recommendation to take aspirin should become stronger. Note: Because treatment based on application of any of the available cardiovascular risk calculators has not been evaluated prospectively, comparison of different calculators is difficult. Because the AHA/ACC CV Risk Calculator is often used to guide lipid treatment, covers patients with diabetes, and estimates both stroke and MI risk clinicians may choose to use the AHA/ACC CV Risk Calculator to estimate cardiovascular risk, and may choose to select aspirin treatment thresholds that align with cholesterol treatment recommendations. Reference: Wolff T, Miller T, Ko S. Aspirin for the Primary Prevention of Cardiovascular Events: An Update of the Evidence for the U.S. Preventive Services Task Force. Evidence Synthesis No. 68. AHRQ Publication No. 09-05129-EF-1. Rockville, Maryland: Agency for Healthcare Research and Quality, March 2009.

Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

2014 National Aspirin Recommendations

Aspirin Therapy for people with non-coronary ASCVD Rationale: Subgroup

A1a. Symptomatic atherosclerotic peripheral arterial disease (claudication, revascularization or end-organ damage)

A1b. Repaired abdominal aortic aneurysm (AAA)

1

Quality of Evidence

Balance of benefits versus harms and burdens

Individual studies’ 1 Jadad scores ranged from 2-5. Results from highquality studies (Jadad ≥4) were similar to overall results. Based on sensitivity analyses of high-quality studies, the GDT considers the evidence to be of high quality

Although not analyzed as a separate sub-population in these analyses, existing evidence in a mixed atherosclerotic PAD population has shown a reduction in nonfatal stroke with no increase in serious bleeding(1).

No direct evidence exists

No direct evidence exists in patients with repaired AAA. As patients with repaired AAA are at high CVD risk(2), the net benefit favors aspirin therapy

Values and Preferences

The GDT believes, because the risk of cardiovascular disease is high, patients would generally value the potential cardiovascular benefit of aspirin higher than the potential risk of serious bleeding. Variation in patient acceptance of aspirin therapy is likely to be low.

The GDT believes, because the risk of cardiovascular disease is high, patients with a history of surgical repair would generally value the potential cardiovascular benefit of aspirin higher than the potential risk of serious bleeding. Variation in patient acceptance of aspirin therapy is likely to be low.

Jadad is a methodological quality scoring system for randomized controlled trials

Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

Resource implications

Recommendation

low

low

A1.For patients with symptomatic atherosclerotic peripheral arterial disease (claudication, revascularization or endorgan damage) or repaired AAA, clinicians should prescribe low-dose (81 mg/day) aspirin therapy. (Strong Recommendation)

2014 National Aspirin Recommendations

Subgroup

Quality of Evidence

A2. Asymptomatic atherosclerotic peripheral arterial disease (includes calcifications or stenosis, abnormalities of carotid IMT, abnormal ABI or AAA, that have had no repair, no revascularization, or no end-organ damage)

High-no serious limitations

A2b. Asymptomatic (unrepaired) AAA

Very low: No direct evidence exists

Balance of benefits versus harms and burdens These analyses show a modest mortality benefit overall, however in subgroup analyses of patients with asymptomatic peripheral arterial disease, evidence fails to show benefit of aspirin, although risk of major bleeding is low. There is no existing evidence demonstrating lack of benefit.

Values and Preferences

Resource implications

Recommendation

low

The GDT believes, because the risk of cardiovascular disease is elevated, patients would generally value the potential mortality benefit of aspirin higher than the potential risk of serious bleeding. Variation in patient acceptance of aspirin therapy is likely to be low

No direct evidence exists in patients with asymptomatic AAA. As patients with asymptomatic AAA are at elevated CVD risk, the net benefit favors aspirin therapy

Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

low

A2. For patients with asymptomatic atherosclerotic peripheral arterial disease (includes calcifications or stenosis, abnormalities of carotid intimal medial thickness (IMT), abnormal anklebrachial index (ABI), and AAA that have had no repair, no revascularization, or no end-organ damage) clinicians may prescribe lowdose (81 mg/day) aspirin therapy. (Weak Recommendation)

2014 National Aspirin Recommendations

Aspirin Therapy for people with CAD Rationale:

2014 Update No new evidence was found, the recommendations remain unchanged. A modification was made to the aspirin recommendation (context was unchanged).

2010 Update No new evidence was found, the recommendations remain unchanged.

2008 Guideline Update Rationale for aspirin dose Because of concerns about the risks of bleeding with higher doses of aspirin, the GDT recommends starting aspirin therapy at 81 to 162 mg of aspirin. The GDT did not believe that patients who are doing well on the higher doses of aspirin needed to be switched to the lower dose range. Other Considerations The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients with Chronic Stable Angina states “Aspirin should be started at 75 to 162 mg per day and continued indefinitely in all patients unless contraindicated.”

2006 Guideline Update No change in the 2004 recommendations has been made as a result of this systematic review.

2004 Guideline Update Supporting Evidence for Antiplatelet therapy versus Placebo The Antithrombotic Trialists’ Collaborative (ATC) meta-analysis(28) of 195 trials of antiplatelet therapy versus controls reported that aspirin, or another antiplatelet drug, reduced the combined outcome of any serious vascular event by ~25% in high risk patients including those with an AMI or ischemic stroke, unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral arterial disease, or atrial fibrillation. In each of these categories of patients, the absolute benefits substantially outweighed the absolute risks of major extra-cranial bleeding. Some differences were reported in proportional risk reductions by subcategory of disease. Supporting Evidence for Aspirin versus Placebo (Including Dose) When compared to placebo, the ATC meta-analysis(28) found aspirin to be an effective antiplatelet agent in the prevention of serious vascular events in high risk patients. Among the Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

2014 National Aspirin Recommendations

trials of higher daily doses of aspirin versus no aspirin, doses of 75 to 150 mg daily were at least as effective as higher doses for long-term prevention. No evidence was cited to support aspirin doses > 1,000 mg for stroke prevention. In those trials reported by the ATC comparing aspirin with control, the proportional increase in the risk of a major extracranial bleed was similar with all daily aspirin doses < 325 mg, with odds ratios in the range of 1.4 to 1.7. In a separate meta-analysis evaluating the benefits and risks of low-dose (50 to 325 mg) aspirin compared to placebo in secondary prevention trials, Weisman(37) reported aspirin to confer a statistically significant reduction in all-cause mortality as well as vascular events and MI. NNT calculations suggest that 1.5 lives are saved for every GI bleed event attributed to aspirin. Supporting Evidence for Aspirin versus Thienopyridine Therapy When any aspirin dose was compared with any other antiplatelet drug the ATC metaanalysis(28) reported a nonsignificant test result for heterogeneity in support of the finding that there were no differences among antiplatelet agents in their effects on serious vascular events (81,731 patients in 166 trials, excluding acute stroke). Among the 19,185 patients with a history of MI, stroke or peripheral artery disease, in the CAPRIE Trial cited by the ATC, (28) a statistically significant reduction of 10% (standard error = 4%) in serious vascular events was found for clopidogrel compared with aspirin. In a separate analysis of the 19,185 CAPRIE Trial participants, Cannon(38) reports clopidogrel significantly reduced the relative risk of AMI (by 19.2%, p = 0.008) compared to aspirin among those patients with ischemic stroke, AMI, or peripheral artery disease. Supporting Evidence for Thienopyridine plus Aspirin Therapy versus Aspirin Alone The CURE trial,(39) a large randomized, controlled trial of 12,562 patients with acute coronary syndrome, without ST-segment elevation, found that clopidogrel plus aspirin reduces the risk of cardiovascular death, MI and stroke, with benefits emerging within 24 hours of initiation of treatment and continuing throughout the three to 12 months (mean was nine months) of the study (RR = 0.82; 95% CI: 0.70 to 0.95, p = 0.009). Supporting Evidence for Low-Dose Aspirin in Patients on ACE Inhibitors See 2004 KP National Heart Failure Guidelines for complete discussion of evidence. These guidelines cite a study(40) which evaluated the effect of aspirin dose in the coadministration of ACE Inhibitors and aspirin in heart failure patients (31% of whom had had an MI) and reported that at low doses (≤ 160 mg) aspirin did not result in increased mortality (HR = 1.02, p = 0.18). Professional Group Recommendations Reviewed Kaiser Permanente, Care Management Institute, Oakland, California, September 2014

2014 National Aspirin Recommendations •

 ACC/AHA Guidelines for Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease: 2001 Update

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 ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

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 ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina  AHA Scientific Statement: Secondary Prevention of Coronary Heart Disease in the Elderly (With Emphasis on Patients > 75 Years of Age)

Other Considerations This updated evidence on the use of antiplatelet agents by patients with CAD is consistent with that presented in the 2002 CMI CAD Guidelines in support of aspirin use. Since July 2001, additional evidence available on multiple dose ranges strengthens the recommendation in 2004 for low-dose aspirin (at 75 to 150 mg) in those who tolerate aspirin. The recommendation remains unchanged to permit use of aspirin in units commonly available. A second recommendation for preferential low-dose aspirin is added for persons taking ACE Inhibitors to address reports of decreased efficacy of ACE Inhibitors with concomitant use of aspirin. The ACC/AHA 2002 Practice Guidelines for secondary prevention in patients with coronary and other vascular disease states: “Start and continue indefinitely 75 to 325 mg/day of aspirin if not contraindicated.” Overall Conclusion from Evidence Because of the reliability and homogeneity of these findings across studies, extrapolation of the evidence to a wide range of high-risk CAD patients is appropriate. Although there is evidence presented which supports the use of thienopyridine therapy (clopidogrel) alone in preference to aspirin as a first line antiplatelet treatment in persons at high risk of vascular events, an analysis of quality adjusted years of life saved (QALY) renders the choice of clopidogrel (in those who tolerate aspirin) prohibitive ($11,000/QALY for aspirin vs. > $130,000/QALY for clopidogrel).(41) Summary of 2002 Rationale: One extensive meta-analysis(7) demonstrated the protective effect of daily aspirin in reducing the odds of a vascular event (nonfatal MI, nonfatal stroke, or vascular death) for patients at high risk of ischemic cardiac events. This meta-analysis showed further benefits from longer treatment periods, but no further benefit from an aspirin dose greater than 325 mg. Two additional clinical trials(8, 9) further support that low-dose aspirin can significantly reduce the incidence of cardiac events. Kaiser Permanente, Care Management Institute, Oakland, California, September 2014